Process for the preparation of pharmaceutical compositions for the sustained release of somatostatin analogs

ABSTRACT

A process for the preparation of injectable pharmaceutical compositions for the sustained release of somatostatin analogs and compositions prepared according to the process. The process may comprise lyophilizing a mixture of lanreotide acetate and acetic acid to form a lyophilizate and hydrating the lyophilizate, wherein the lyophilization is performed only once.

This application is a continuation of U.S. application Ser. No.13/522,297, filed Dec. 7, 2012, which is the U.S. National Phase ofInternational Patent Application No. PCT/EP2011/000069, filed Jan. 11,2011, which claims priority to U.S. Provisional Application No.61/294,644, filed Jan. 13, 2010. The contents of each of the foregoingapplications are hereby incorporated by reference in their entirety.

The invention relates to a process for the preparation of pharmaceuticalcompositions for the sustained release of somatostatin analogues and topharmaceutical compositions prepared according to said process.

The invention further relates to pharmaceutical compositions for thesustained release of the somatostatin analogue lanreotide.

Many peptide treatments require continuous or repeated administration inthe patient over an extended period of time. As repeated injectionscause both inconvenience and discomfort to the patient, sustainedrelease preparations are desirable and have been the subject ofdevelopment efforts.

Various processes are known for the preparation of sustained release ofpeptides. However, the processes are often relatively complex and maynot consistently produce the same product.

International Patent Publication WO 2004/030650 discloses a preparationfor the sustained release of a GnRH antagonist. In contrast to thepresent application is gozarelix [INN name], an antagonist of releasingfactor luteinizing hormone (LHRH), used in patients suffering frombenign prostatic hyperplasia (BPH) previously known by its developmentcode D-63153. The publication discloses reconstituting a lyophilizedpeptide with a low-concentration inorganic salt solution to aconcentration of from 5 mg to 50 mg of peptide per milliliter.Administration of the resulting preparation is contemplated up to twohours after the reconstitution.

U.S. Pat. No. 5,595,760 describes solid and semi-solid pharmaceuticalcompositions intended for the sustained release of peptides, whichcompositions are composed of a gellable and water-soluble peptide saltoptionally combined with an appropriate monomeric excipient. Thesecompositions gel after administration to a patient and allow a sustainedrelease over a period of at least three days.

International Patent Publication WO 99/48517 discloses a solid orsemi-solid pharmaceutical composition comprising a gellable andwater-soluble peptide salt. The process for the preparation of thecomposition involves two lyophilization steps and the addition of anacid to regulate the final pH is not disclosed.

The applicant has now discovered that a simpler process involving asingle lyophilization step may be employed to produce compositionsaccording to the invention.

It is an object of the invention to provide a simpler process for thepreparation of injectable compositions for the sustained release ofsomatostatin analogues. It is a further object of the invention toproduce compositions consistently having a pH within a relatively narrowrange.

A subject of the present invention is therefore a process for thepreparation of an injectable sustained release pharmaceuticalcomposition, comprising the steps of:

-   -   combining a gellable somatostatin analogue salt and an aqueous        acid solution;    -   lyophilizing the resulting mixture only once; and    -   hydrating the lyophilizate;        wherein the final pH of the composition ranges between pH 5 to        7.

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

The term “pharmaceutically acceptable” means in this contextphysiologically well-tolerated by a mammal or a human.

The term “gellable” means the capability of a compound to formsemi-solid products, with viscosity suitable for parenteraladministration, when mixed with pure water, aqueous solutions containingand acid or basic agent suitable to adjust the pH or other solventssuitable for parenteral administration in humans.

Somatostatin analogue is understood as meaning a somatostatin derivativeor analogue such as lanreotide as described in the European Patent EP215171, or a somatostatin analogue such as that described in the U.S.Pat. No. 5,552,520 (this patent itself includes a list of other patentsdescribing somatostatin analogues, which are incorporated in the presentapplication by way of reference).

The somatostatin analogue used for the invention may be selected fromthe group comprising lanreotide [BIM 23014], octreotide and BIM-23244, asomatostatin receptor subtype 2- and 5-selective analogue.

The salts of the somatostatin analogue which can be used for theinvention are preferably pharmaceutically acceptable salts of organicacids, such as those of acetic, lactic, malic, ascorbic, succinic,benzoic, methanesulphonic or toluenesulphonic acids, or pharmaceuticallyacceptable salts of inorganic acids, such as those of hydrochloric,hydrobromic, hydriodic, sulphuric or phosphoric acids. In particular,they can be acetates of the somatostatin analogue.

The somatostatin analogue lanreotide, also known by the development codeBIM 23014, is sold in the form of lanreotide acetate under the trademark SOMATULINE®. Lanreotide acetate is a synthetic cyclic octapeptideanalog of the natural hormone somatostatin. Lanreotide acetate ischemically known as[cycloS-S]-3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-Lcysteinyl-L-threoninamide,acetate salt. Its molecular weight is 1096.34 (base) and its developedformula is:

The somatostatin analogue BIM 23244 is the compound DPhe-c(Cys-3ITyr-DTrp-Lys-Val-Cys)-Thr-NH₂ (C₅₀H₆₆IN₁₁O₁₀S₂).

In a preferred embodiment, the somatostatin analogue used for theinvention is selected from the group comprising lanreotide [BIM 23014]and octreotide.

In a preferred embodiment, the somatostatin analogue is lanreotide. In apreferred embodiment, the somatostatin analogue is octreotide.

In a preferred embodiment, the acid is acetic acid.

In a preferred embodiment, the somatostatin analogue is lanreotide andthe acid is acetic acid.

The acetic acid used in a preferred embodiment of the invention may bein the form of glacial acetic acid, and may have a purity of 95% to99.7% or higher, preferably have a purity of 95%, 98%, 99%, 99.7% orhigher, and more preferably 99.7% or higher.

In a preferred embodiment, the final step in the inventive processenables the addition of acid, as necessary, to produce compositions ofrelatively consistent pH. Hence the water used to hydrate thelyophilizate preferably contains acid at a concentration suitable forproviding the requisite final pH. More preferably water used to hydratethe lyophilizate preferably contains acetic acid at a concentrationsuitable for providing the requisite final pH, and/or to render theanhydrous acetate content of the pharmaceutical composition of 9±2% byweight. More preferably water used to hydrate the lyophilizatepreferably contains acetic acid at a concentration suitable forproviding the requisite final pH, and/or to render the anhydrous acetatecontent of the pharmaceutical composition 9.7±0.3% by weight.

This aspect of the invention has the advantage of facilitating bettercontrol over the pH, providing compositions of more consistent final pH.Reducing experimental deviations in the final pH is important. As the pHgoverns a number of key parameters including the solubility of the API(active pharmaceutical ingredient) in the pharmaceutical composition.Therefore, the viscosity of the formulation also depends on the pH andconsequently, the force required to inject the composition andsolubility of the drug substance within the pharmaceutical composition.Reducing the force required to inject the composition facilitates theuse of syringe needles of smaller diameter which improves convenience ofuse. The solubility of the drug substance governs the formation of thedepot at the injection site. Once formed the API (active pharmaceuticalingredient) is slowly released from the depot by dissolution and passivediffusion to the surrounding tissue.

In a further preferred embodiment, in the lyophilization step, thetemperature of the mixture during the lyophilization is preferably:

-   -   initially reduced from room temperature to 2° C.±1° C. and then        retained constant;    -   further reduced from 2±1° C. to −40±5° C. and then retained        constant;    -   initially increased from −40±5° C. to 25±5° C. and then retained        constant; and    -   further increased to 35±5° C. and then retained constant.

In a further preferred embodiment, the temperature of the mixture duringthe lyophilization step is successively:

-   -   step a: initially reduced from room temperature to 2° C.±1° C.        and then retained constant;    -   step b: further reduced from 2±1° C. to −40±5° C. and then        retained constant;    -   step c: initially increased from −40±5° C. to 25±5° C. and then        retained constant; and    -   step d: further increased to 35±5° C. (step d) and then retained        constant.

With regard to the pressure during lyophilization, after the temperatureof the mixture is reduced, the atmospheric pressure is preferablyreduced to 20±5 μbar and the atmospheric pressure preferably remainsconstant as the temperature of the mixture increases.

With regard to timing, the duration of the lyophilization process ispreferably at least 60 hours. More specifically, during thelyophilization step, the temperature of the mixture is preferably:

-   -   initially reduced over up to 30 minutes, preferably up to 10        minutes, and then retained constant for 3±1 hours;    -   further reduced over up to 15 minutes, preferably up to 10        minutes, and then retained constant for 3.5±1 hours;    -   initially increased over 20±5 hours and then retained constant        for at least 40 hours; and    -   further increased over 1±0.5 hours and then retained constant        for at least 16 hours.

More specifically, during the lyophilization step, the temperature ofthe mixture is preferably:

-   -   during step a: initially reduced over up to 30 minutes,        preferably up to 10 minutes, and then retained constant for 3±1        hours;    -   during step b: further reduced over up to 15 minutes, preferably        up to 10 minutes, and then retained constant for 3.5±1 hours;    -   during step c: initially increased over 20±5 hours and then        retained constant for at least 40 hours; and    -   during step d: further increased over 1±0.5 hours and then        retained constant for at least 16 hours.

In another preferred embodiment, 25±2 g/l lanreotide base and 15±2% byweight acetic acid are combined in the first step.

In yet another preferred embodiment, the composition comprises water inan amount less than 50% of the amount needed to completely dissolve thelanreotide salt and the proportion of water is adapted to give thecomposition a semi-solid consistency. Preferably, where possible, theamount of water added will be less than 30% and more preferably lessthan 10% of the amount needed to dissolve the somatostatin analogue saltcompletely.

In a preferred embodiment the final pH of the composition will rangefrom pH 5 to 7. More preferably it will range from pH 5.5 to 6.5. Morepreferably it will range from pH 5.8 to 6.4. More preferably it willrange from pH 5.9 to 6.1

Another subject of the present invention is a pharmaceutical compositionprepared according to the process described above.

The composition preferably has an anhydrous acetate content of 7.5±2.5%by weight. Preferably, the composition has an anhydrous acetate contentof 9±2% and more preferably, the composition has an anhydrous acetatecontent of 9.7±0.3% by weight. More preferably, the composition has ananhydrous acetate content of 9.1 to 10.5% by weight.

In a preferred embodiment, the composition is capable of releasing thelanreotide over a period of at least 15 days. Preferably, thecomposition is capable of releasing the lanreotide over a period of atleast 28 days. In a preferred embodiment, the composition is capable ofreleasing the lanreotide over a period of at least 1 month, and morepreferably approximately 2 months (56 days), and more preferably 2months.

In another preferred embodiment, the composition comprises between 15 to35%, by weight of lanreotide base. In another preferred embodiment, thecomposition comprises between 20 and 35% by weight lanreotide base.Preferably, the composition comprises 25±5% by weight lanreotide base.More preferably the composition comprises 24.6±2.5% by weight oflanreotide base. More preferably, the composition comprisesapproximately 24.6% by weight of lanreotide base.

The composition is preferably suitable for use after storage at between2 and 8° C. for more than 12 months, preferably for more than 24 months.The composition is preferably suitable for use after storage at 25° C.for 6 months.

As described above, the invention relates in one aspect to a process forthe preparation of an injectable sustained release pharmaceuticalcomposition comprising a gellable somatostatin analogue salt and anaqueous acid. The process used to prepare the pharmaceuticalcompositions of the invention involves a single lyophilization.

It has been found that the pH of the composition effects both itsinjectability and its release rate. Injectability can be measured eitherin terms of viscosity (with a higher viscosity resulting in a decreasein injectability), or in terms of flow rate (with a higher flow rateresulting in an increase in injectability). Release rate can be measuredby conducting in vitro release tests to determine the percentage of thesomatostatin analogue released over time.

Studying the viscosity, flow rate and release rate of a compositioncontaining a given somatostatin analogue enables an acceptable pH rangefor that somatostatin analogue to be determined.

As previously mentioned, in one embodiment, the somatostatin analogue islanreotide and the aqueous acid is aqueous acetic acid. In thisembodiment, the pH of the composition has been found to be directlyproportional to the concentration of acetic acid. It follows that theoptimum acetic acid concentration can be calculated from the optimum pH.

A preferred process of the invention involves combining the lanreotidebase and the acetic acid, lyophilizing the resulting mixture once, andhydrating the lyophilizate. Detailed conditions under which the processcan be performed are set out below; however, the conditions may bevaried, for example, when different somatostatin analogues are employed.

The lanreotide base and acetic acid may be combined in apre-lyophilisation pool which is then loaded into trays. In a preferredaspect the trays are 1.5 or 2 mm thick and the depth of the solution inthe trays is 1.2 mm thick or less. The depth of the solution in thetrays must be controlled as it has an influence on the final acetateconcentration of the pharmaceutical composition.

Prior to the lyophilization, the concentration of lanreotide base ispreferably between 20 and 30 g/l, more preferably between 23 and 27 g/land most preferably 25 g/l, and the concentration of acetic acid ispreferably less than 20%, more preferably between 13 and 17% and mostpreferably 15%.

The lyophilization may be carried out under conventional conditionsknown to a person skilled in the art.

In a preferred embodiment, the lyophilization process may commence withcooling the solution in the trays to a temperature between roomtemperature and the temperature at which the solution freezes,preferably between 1 and 5° C. or more preferably 2° C. The temperaturemay then remain constant for at least one hour, preferably between 2 and4 hours or most preferably 3 hours. This preliminary cooling stepenables the subsequent freezing step to occur more quickly which, inturn, ensures that the frozen ice lattice is more homogeneous.

The lyophiliser shelves may then be further cooled, preferably to lessthan −20° C., more preferably to less than −30° C., and most preferablyto −40±5° C. This cooling step should be completed as quickly aspossible, preferably over up to 15 minutes and more preferably over upto 10 minutes or less. The resulting solid is preferably retained at aconstant temperature for at least 2 hours, preferably between 2.5 and4.5 hours, and most preferably for 3.5 hours. The mixture must be cooledfor sufficient time so that the entire mixture is frozen prior tosublimation.

The sublimation process may commence with the application of a vacuum,preferably between to 15 to 25 μbar, or more preferably to 20 μbar. Thetemperature of the shelves may then be initially increased, preferablyover at least 10 hours, more preferably between 15 and 25 hours and mostpreferably 20 hours, preferably to between 20 and 30° C., morepreferably to 25° C. The temperature of the solution may then be keptconstant, preferably for at least 20 hours, more preferably for at least40 hours. This primary drying stage removes unbound moisture and aceticacid.

The temperature of the mixture may then be further increased, preferablyover at least 15 minutes, more preferably between 0.5 and 1.5 hour, mostpreferably 1 hour, to a temperature preferably between 30 and 40° C.,more preferably 35° C. To complete the lyophilization stage, thetemperature of the mixture can be retained constant, preferably for atleast 10 hours, more preferably at least 16 hours. This secondary dryingstage removes adsorbed moisture and acetic acid.

The lyophilizate resulting from this preferred process is lanreotideacetate having an anhydrous acetate content of less than 10% in weightand preferably less than 9.6%.

The final stage of the process involves hydrating the lyophilizate withwater, preferably water for injection.

An equipment consisting of two syringes (cylinders) connected via athree-way valve may be employed to mix the optionally acidified waterfor injection and the lanreotide acetate. With regard to the device, aperson skilled in the art may also usefully consult International PatentPublication WO 96/07398. If such equipment is employed, a vacuum isapplied via the three-way valve to the syringe (cylinder) containing thelanreotide acetate powder lyophilizate to reduce the air content withinthe powder. The water in the second cylinder may then be introduced intothe syringe (cylinder) containing the lanreotide acetate, via thethree-way valve. The lanreotide acetate may then undergo statichydration, preferably for at least two hours. In order to homogenize theresulting dispersion, the content of the syringe (cylinder) is passedvia the valve to the other syringe (cylinder), and this process may berepeated with the reciprocating movement of the two pistons assisted byan electric mixer. The force used to depress each piston may beincreased during the mixing process, as the solution becomes moresaturated.

As previously mentioned, if the pH of the lyophilizate is above thetargeted pH, acid may be added to water for injection prior to thehydration, in an amount suitable for providing the requisite pH in thepharmaceutical composition. The acid used for this purpose is preferablyacetic acid.

An important aspect of the invention is the selection of the mostappropriate target pH for the composition. Experiments have shown thatpH is directly linked to acetic acid concentration, and that theserelated factors influence both the injectability and the solubility ofthe drug substance in the pharmaceutical composition With regard to theinjectability, an increase in the pH leads to a decrease in the flowrate and an increase in the syringe injection force (SIF), both of whichresult in decreased injectability. With regard to the release rate,lanreotide acetate concentration (and consequentially pH) influences thesolubility of the drug substance within the composition. The solubilityof the drug substance governs the formation of the depot at theinjection site. An increase in the pH leads to a faster formation of thedepot and consequently to a better control of the burst effect in the PKprofile. Furthermore, the effect of pH on the solubility of the activesubstance impacts on the in vitro release test developed for the routinequality control of the drug product. An increase in the pH leads to adecrease in the release profile of the composition.

It follows that in order to produce a composition which is easy toinject and which releases the active ingredient over an extended periodof time, a pH must be selected which provides an appropriate compromisebetween the competing factors injectability and release rate.

In the embodiment where the somatostatin analogue is lanreotide and theacid is acetic acid, experiments have determined that the mostappropriate pH range is 5.8 to 6.4, which corresponds to an anhydrousacetate content of the pharmaceutical composition of 9.1 to 10.5% byweight. The water may be conveniently acidified in the manner describedabove if the concentration of acetate in the solid lyophilizate is suchthat the pH of the pharmaceutical composition would otherwise be abovethe acceptable pH range. Adding acetic acid to the water enables theanhydrous acetate content to be increased to the targeted concentration.

The proportion of somatostatin analogue in the compositions according tothe invention will be determined by the release time which it is desiredto achieve, but it cannot exceed a maximum value corresponding to thelimiting concentration at which the solid or semi-solid composition canbe injected with a syringe fitted with a needle of customary diameter.

Preferably the compositions of the invention comprise from 18.3 to 42.7%by weight of lanreotide acetate. Preferably the compositions of theinvention based on lanreotide acetate will comprise from 25 to 35%,preferably from 25 to 30%, corresponding to 20.5 to 24.6% by weight ofpure lanreotide. In a preferred embodiment, the compositions of theinvention will comprise 30±3% by weight of lanreotide acetate,corresponding to 24.6±2.5% by weight of lanreotide base.

A range of 25 to 35% by weight of lanreotide acetate in the compositioncorresponds to a range of 20.5 to 28.7% by weight of pure lanreotidebase in the composition. A range of 24.4 to 42.7% by weight oflanreotide acetate in the composition corresponds to a range of 20 to35% by weight of pure lanreotide base in the composition. A range of24.4 to 36.6% by weight of lanreotide acetate in the compositioncorresponds to a range of 20 to 30% by weight of pure lanreotide base inthe composition.

The semi-solid compositions according to the invention are for use inthe pharmaceutical field. The compositions according to the inventionmay be administered to a patient, for example, by way of injection usinga device such as those described in U.S. Pat. No. 6,953,447.Compositions according to the invention may easily be injected withneedles of gauge approximately 17 or 18, which corresponds to aninternal diameter of about 1 mm.

Unless defined otherwise, all the technical and scientific terms usedhere have the same meanings as those commonly understood by an ordinaryspecialist in the field to which this invention belongs. All thepublications, patent applications, patents and other referencesmentioned here are incorporated by way of reference.

The following examples are given in order to illustrate the aboveprocedures and must not be considered as limiting the scope of theinvention.

Experimental Part

The general steps employed in the examples are set out below. Not all ofthe steps were employed in all of the examples. The general steps arefollowed by detailed information on each of the examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of syringe injection force (SIF) (in Newtons) versus pHfor compositions prepared by a process according to the inventionincluding a single lyophilization (represented by filled circles) andcompositions prepared by a process including two lyophilizations(represented by filled squares).

FIG. 2 is a plot of flow rate (micro-liters per minute) versus pH forcompositions prepared by a process according to the invention includinga single lyophilization (represented by filled circles) and compositionsprepared by a process including two lyophilizations (represented byfilled squares).

FIG. 3 is a plot showing the percentage of lanreotide acetate releasedafter 2.75 hours versus pH during an in vitro test of compositionsprepared by a process according to the invention including a singlelyophilization (represented by filled circles) and compositions preparedby a process including two lyophilizations (represented by filledsquares).

FIG. 4 is a plot showing the percentage of lanreotide acetate releasedafter 9.25 hours versus pH during an in vitro test of compositionsprepared by a process according to the invention including a singlelyophilization (represented by filled circles) and compositions preparedby a process including two lyophilizations (represented by filledsquares).

FIG. 5 is a plot showing the percentage of lanreotide acetate releasedafter 24.25 hours versus pH during an in vitro test of compositionsprepared by a process according to the invention including a singlelyophilization (represented by filled circles) and compositions preparedby a process including two lyophilizations (represented by filledsquares).

FIG. 6 is a plot showing the relation between the acetate content (AcOHlevel) and the pH of the composition. Data of pH are plotted in functionof the acetate content in % (w/w) of the active substance.

COMBINING LANREOTIDE ACETATE AND AQUEOUS ACETIC ACID, FOLLOWED BY FIRSTLYOPHILISATION

A pre-lyophilization pool was prepared by adjusting the concentration ofpure Lanreotide [BIM 230141] to 25±2 g/l in an aqueous solution of 15%acetic acid solution. The pool was loaded into a metal tray and placedin a lyophiliser whose shelves were cooled from room temperature to 2°C. over 10 minutes and then held at this temperature for 3 hours. Thecooled mixture was then frozen to −40° C. over 10 minutes and then heldat this temperature for 2.75 hours.

To effect the lyophilisation, a vacuum to 20 μbar was applied andmaintained while the lyophiliser shelves were heated from −40° C. to 25°C. over 20 hours, held at this temperature for a further 63.3 hours andfurther heated to 35° C. for 23 hours.

Optional Acidification

Water for injection was acidified with glacial acetic acid.

Hydration of the Lyophilizate

The lanreotide acetate lyophilizate powder was combined with acidifiedwater for injection to a specified concentration of pure lanreotideusing the following steps. The lanreotide acetate and water were weighedand placed into two separate cylinders, fitted with pistons and linkedtogether via a three-way valve. Prior to hydration, a vacuum of between100 and 600 μbar was applied to the cylinder containing the lanreotideacetate powder via the three-way valve. The water was then introducedinto the cylinder containing the lanreotide acetate, again via thethree-way valve. The lanreotide acetate then underwent static hydrationfor at least two hours. The dispersion was then homogenised by passingthe contents back and forth between the two cylinders via thethree-way-valve, using the pistons. The process yielded a lanreotideacetate supersaturated gel.

SUMMARY OF EXAMPLES 1 TO 9

A summary of the specific conditions of each example appears in Table 1,below.

TABLE 1 Example AcOH (% w/w) Lanreotide No. Batch API Added Total (%w/w) pH 1 04K TS 9.9 0.0 9.9 24.83 6.01 2202 2 DS 9.5 0.0 9.5 24.82 6.25361/022 3 04K TS 9.2 0.0 9.2 24.75 6.41 2205 4 04K TS 8.2 0.0 8.2 24.706.86 2204 5 04K TS 8.2 0.5 8.7 24.73 6.61 2204 6 04K TS 8.2 2.5 10.724.60 5.78 2204 7 FFD 04K 7.5 1.2 8.7 24.88 6.51 TS 2205 8 N006.21 9.71.3 11.0 24.88 5.73 00006 9 FFD 04K 7.5 0.0 7.5 24.87 6.95 TS 2205

Three columns are presented under the “AcOH” heading, each of whichrelates to weight percentage of acetic acid. The “API” column identifiesthe amount of acetic acid in the lyophilizate (also termed the activeprincipal ingredient), before hydration. The “Added” column identifiesthe amount of acetic acid, if any, added to the water used in thehydration process. A zero in the API column indicates that the optionalacidification step was not employed. The Total column provides the totalamount of acetic acid present in the composition, made up of the sum ofthe API and added columns.

The Lanreotide column provides the weight percentage of lanreotidepeptide in the finished composition. The pH column provides the pH valueof the finished composition.

The examples 1-6 correspond to compositions prepared by a processaccording to the present invention and including a singlelyophilization; the examples 7-9 correspond to compositions prepared bya process including two lyophilizations according to the process asdescribed in the PCT application WO 99/48517.

CHARACTERISTICS OF THE COMPOSITIONS PREPARED IN EXAMPLES 1 TO 9

Properties of the compositions prepared according to Examples 1 to 9 aretabulated in Table 2, below, and graphed in FIGS. 1 to 6.

TABLE 2 Flow Example SIF Mean Routine IVT Mean (% released) No. Mean (N)(μl/min) Q (2.75 h) Q (9.25 h) Q (24.25 h) 1 18.9 96.8 18.7 53.3 92.5 221.4 83.0 17.5 51.2 91.6 3 21.8 83.5 17.3 48.8 89.4 4 30.3 9.9 15.8 46.087.1 5 25.4 34.0 18.4 52.1 92.0 6 17.2 144.8 19.5 54.7 94.7 7 24.4 56.117.0 48.2 88.3 8 17.3 136.9 20.7 57.6 95.2 9 26.7 1.0 15.7 45.5 84.5

Injectability of the compositions was measured both in terms of thestrength required to discharge the syringe (syringe injection force orSIF) and the viscosity of the compositions, measured in terms of flowrate.

The flow rate method was developed based upon the principles of thereference NF EN ISO 1133: “Determination of the melt mass flow rate(MFR) and the melt volume flow rate (MVR) of thermoplastics”. In thistechnique, the viscosity of the solution is determined indirectly, undertemperature-controlled conditions, by measuring the flow throughout astandarised stainless-steel test syringe while a constant pressure isapplied. The flow of the supersaturated gel through the syringe (whichis proportional to the viscosity) is measured and expressed as aflow-rate (μl/min).

Syringe injection force (SIF) test was developed to assess the maximumforce needed to discharge, at a constant displacement rate (200 mm/min),the formulation contained in the finished drug product syringemaintained in vertical position.

Release of the active ingredient was measured using an in vitro test(IVT), in which the percentage of the active component released (Q) wasmeasured after 2.75 h, 9.25 h and 24.25 h. The in vitro released testwas object of an specific development bearing in mind the specialcharacteristics of the formulation for which none of the conventional invitro dissolution apparatus was applicable. As a result, a small drugproduct holding device was developed to retain the formulation in adialysis membrane. The in vitro dissolution profile is obtained insaline solution by using the pharmacopoeial dissolution (basket)apparatus, as described in the USP test <711> Dissolution, apparatus 1and in the Eur.Pharm. 2.9.3 monograph.

In FIG. 1, syringe injection force (SIF) is plotted against pH. Thegraph demonstrates that as the pH increases, the SIF also increases, andthe extent of the SIF increase is not dependent on whether the singlelyophilization process or double lyophilization process was employed.

In FIG. 2, flow rate is plotted against pH. The flow rate is inverselyproportional to pH in that as pH increases, the flow rate decreases. Aswith acetic acid concentration and SIF, the flow rate parameter is notinfluenced by whether the single lyophilization process or doublelyophilization process was employed.

In FIGS. 3, 4 and 5, the proportion of the active ingredient released isplotted against pH during an in vitro test of the compositions, measuredafter 2.75 hours, 9.25 hours and 24.25 hours, respectively. The graphsdemonstrate that the release rate decreases with increasing pH when theconcentration is kept constant.

EXAMPLE 10: PREFERRED PROCEDURE FOR THE PREPARATION OF COMPOSITIONSACCORDING TO THE INVENTION

A pre-lyophilization pool was prepared by dissolving 25 g/l purelanreotide [BIM-23014] in an aqueous solution of 15% acetic acidsolution. The pool was loaded into a hollow metal tray and cooled fromroom temperature to 2° C. over 10 minutes and then held at thistemperature for 3 hours. The cooled mixture was then frozen to −40° C.over 10 minutes and then held at this temperature for 2.75 hours. Avacuum to 20 μbar was applied and maintained while the mixture washeated from −40° C. to 25° C. over 20 hours and further heated to 35° C.for 16.75 hours.

Water for injection was acidified with glacial acetic acid sufficient toprovide a final anhydrous acetate content of 9.6% to 10%. The acidifiedwater and lanreotide acetate were then combined to a concentration of24.6% pure lanreotide and 9.6% to 10% anhydrous acetate as follows: thelanreotide acetate and water were weighed and placed into two separatecylinders, fitted with pistons and linked together via a three-wayvalve. Prior to hydration, a vacuum of between 100 and 600 μbar wasapplied to the cylinder containing the lanreotide acetate powder via thethree-way valve. The water was then introduced into the cylindercontaining the lanreotide acetate, again via the three-way valve. Thelanreotide acetate then underwent static hydration for at least twohours. The dispersion was then homogenised by passing the contents backand forth between the two cylinders, using the pistons. The processyielded a lanreotide acetate supersaturated gel of pH 6.2.

While the present invention has been described with reference to onespecific embodiment, it will be appreciated that various modificationsand changes could be made without departing from the scope of theinvention.

The invention claimed is:
 1. A process for preparing an injectablesustained release pharmaceutical composition, the process comprising thesteps of: lyophilizing a mixture comprising a somatostatin analog saltand an aqueous acid solution in a stepwise temperature pattern, whereinthe temperature is: initially reduced from room temperature to 1 to 3°C.; then reduced from to −45 to −35° C.; then increased to 20 to 30° C.and then increased to 30 to 40° C.; and hydrating the resultinglyophilizate; wherein: the lyophilization is performed only once; andthe final pH of the composition is from 5 to
 7. 2. The process of claim1, wherein the somatostatin analog is lanreotide.
 3. The process ofclaim 1, wherein the acid is acetic acid.
 4. The process of claim 1,wherein the final pH of the composition is from 5.8 to 6.4.
 5. Theprocess of claim 1, wherein the aqueous acid solution contains aceticacid at a concentration suitable for providing the requisite final pH.6. The process of claim 1, wherein the lyophilizate is hydrated with asolution containing acetic acid at a concentration suitable to provide acomposition having an anhydrous acetate content of 9.1 to 10.5% byweight.
 7. The process of claim 2, wherein a 23 to 27 g/l lanreotidecomposition and a 13 to 17% by weight acetic acid composition arecombined to form the mixture.
 8. The process of claim 1, wherein thelyophilization occurs over a period of at least 40 hours.
 9. The processof claim 1, wherein: the temperature of the mixture is: reduced fromroom temperature to 1 to 3° C. over a period of up to 30 minutes andthen retained constant for 2 to 4 hours; further reduced to −45 to −35°C. over a period of up to 15 minutes and then retained constant for 2.5to 4.5 hours; increased to 20 to 30° C. over a period of 15 to 25 hoursand then retained constant for at least 40 hours; and further increasedto 30 to 40° C. over a period of 0.5 to 1.5 hours and then retainedconstant for at least 16 hours.
 10. The process of claim 1, wherein,after the temperature of the mixture is reduced to −45 to −35° C., theatmospheric pressure is reduced to 15 to 25 μbar and remains constant asthe temperature of the mixture increases.
 11. The process of claim 2,wherein the lyophilizate is hydrated by dissolving it in water that isless than 50% of the amount needed to completely dissolve the lanreotidesalt.
 12. A sustained-release pharmaceutical composition preparedaccording to claim
 1. 13. The composition of claim 12, the compositionbeing capable of releasing the lanreotide in vivo over a period of atleast 15 days.
 14. The composition of claim 12, wherein the compositioncomprises from 15 to 35% by weight lanreotide base.
 15. The compositionof claim 12, wherein the composition is suitable for use after storagefor more than 12 months at a temperature of between 2 and 8° C.
 16. Theprocess of claim 2, wherein water is used to hydrate the lyophilizate.17. The process of claim 2, wherein the lyophilizate is hydrated with asolution containing acetic acid at a concentration suitable to provide acomposition having an anhydrous acetate content of 7 to 11% by weight.